Synthesis and spectroscopic studies of new quasi podands from bile acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.06.096

A new method for the synthesis of esters of bile acid derivatives is described. These new compounds are characterized by spectroscopic and PM5 methods. Estimation of the pharmacotherapeutic potential has been accomplished for the compounds synthesized on the basis of prediction of activity spectra for substances (PASS).

Full text of DOI:10.1016/j.tetlet.2013.06.096

Tetrahedron Letters 54 (2013) 4700–4704
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Tetrahedron Letters
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Synthesis and spectroscopic studies of new quasi podands from bile
acid derivatives
⇑
Tomasz Pospieszny , Hanna Koenig, Bogumił Brycki
Laboratory of Microbiocides Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan´, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for the synthesis of esters of bile acid derivatives is described. These new compounds are
characterized by spectroscopic and PM5 methods. Estimation of the pharmacotherapeutic potential has
been accomplished for the compounds synthesized on the basis of prediction of activity spectra for sub-
stances (PASS).
Received 5 April 2013
Revised 7 June 2013
Accepted 21 June 2013
Available online 29 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Bile acids
Podands
1,8-Diazabicycloundec-7-ene (DBU)
Prediction of activity spectra for substances
(PASS)
Steroids are a large class of natural compounds, many of which
display very important roles in plants and animals. Steroids are not
only constituents of the cell membrane in eukaryotes (e.g., choles-
terol and ergosterol), but they are also the main sex hormones in
mammals (e.g., testosterone and estrogens) and plants (e.g., brassi-
nosteroids). They also play important roles in regulating metabolism
(e.g., bile acids and vitamin D).1 Bile acids (e.g., lithocholic, deoxy-
cholic and cholic) and their derivatives are attractive for synthetic
chemists because they have a large, rigid, and curved skeleton. More-
over, they possess chemically different polar hydroxy groups
form stable complexes with monovalent cations.7 Podands show
relatively low cation selectivity during complex formation as well
as limited capacity to recognize selectively chiral compounds as a
result of their geometry.7,8 For this reason, semi-synthetic
dipodands and tripodands have been obtained from the naturally
occurring polyether ionophores, lasalocid acid, monensin A, and
1,6-dibromohexane, or 1,3,5-tris(bromomethyl)benzene.9 Further-
more, bile acid derivatives based on the structure of 1,3,5-benzen-
etricarboxylic acid form a hydrophilic cavity and can recognize
hydrophilic hosts in organic solvents. These molecules bind nitro-
(3a,3a,7a
and 3a,7a,12a) and amphiphilic properties. As a result
phenols, triethanolamine, amino acids, and octyl-glucosides.10
A
of the unique structural elements, bile acids are very prominent in
the study of molecular recognition, host–guest chemistry, and bio-
mimetic chemistry.2 They play important roles in supramolecular
chemistry and as drugs in pharmacology.2 Bile acids themselves have
been used as building blocks for the design and construction of new
molecular receptors that are able to recognize guest molecules of di-
verse chemical nature.3 Bile acid dimers can be used for the synthesis
of macrocyclic compounds as artificial receptors4 and some deriva-
tives of bile acids are very good organogelators.5
On the other hand, classical podands have acyclic structures, in
which polyether chains are linked to the same binding center,
which can be different atoms, for example, N, P, or S. In view of
their specific properties, these simple compounds are so-called
open-chain simple analogues of crown ethers and cryptands.6 Sim-
ilar to the above compounds, podand hosts are generally able to
large group of anion receptors based on the structure of cholesterol
and bile acids belongs to the cholapods.6 Satyanarayana and Maitra
have previously described the synthesis of steroid dendrimers.11
Oligomers have been obtained from reactions of sodium salts of
bile acids with 1,3,5-tris(bromomethyl)benzene in DMF. These
oligomers facilitate the transport of molecules of different sizes
and structures, and with various functional groups, into nonpolar
solvents.11
However, to the best of our knowledge, no work has been pub-
lished on the synthesis or the physicochemical properties of bile
esters of 1,3,5-tris(bromomethyl)benzene or 1,2,4,5-tetrakis(bro-
momethyl)benzene and
3a
-acetoxy-5b-cholanic acid,
3a,12a-
diacetoxy-5b-cholanic acid, and 3
a
,7 ,12 -triacetoxy-5b-cholanic
a
a
acid. Connection of acetate groups to bile acids can increase the
probability of formation of complex compounds.
This Letter reports the synthesis and physicochemical proper-
ties of new esters of bile acid derivatives and 1,3,5-tris(bromo-
methyl)benzene or 1,2,4,5-tetrakis(bromomethyl)benzene. The
⇑
Corresponding author. Tel.: +48 618291307.
E-mail address: tposp@amu.edu.pl (T. Pospieszny).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.096

T. Pospieszny et al. / Tetrahedron Letters 54 (2013) 4700–4704
4701
syntheses of compounds 7–13 are shown in Scheme 1. We used the
direct alkylation reaction of the carboxylate ions of bile acids with
shows, however, a remarkable solvent dependence. The highest
yields of the respective esters were obtained in nonpolar solvents
such as toluene. This is probably due to the very good solubility
of the substrates and products in solvents with low electrical
permittivity.
1,3,5-tris(bromomethyl)benzene
or
1,2,4,5-tetrakis(bromo-
methyl)benzene using
a
catalytic amount of 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) in dry toluene.12 DBU is a strong
base and a weak nucleophile (nonnucleophilic base), and therefore
generates carboxylate ions easily. This esterification method
The potential pharmacological activity of the synthesized com-
pounds was investigated using computer-aided drug discovery ap-
21
18
19
24
12
CO2H
CO2H
Ac2O, Py, DMAP
R2
R2
7
R1
R1
3
(1) R1 = R2 = H
) R1 = R2 = H
4
(
(5) R1= H, R2 = OAc
(6) R1 = R2 = OAc
(2) R1= H, R2 = OH
OH
OAc
) R1 = R2 = OH
3
(
i) DBU, PhMe, temp.
ii) 1,3,5-tris(bromomethyl)benzene or
1,2,4,5-tetrakis(bromomethyl)benzene
O
O
O
O
O
O
O
O
O
O
O
O
O
O
R3
R3
R2
R3
R3
R2
R3
R2
R3
R2
R2
R3
R1
R2
R2
R1
R1
R1
R1
(7) R1 = OAc, R2 = R3 = H
R1
(8)
R
1 = R3 = OAc, R2 = H
(
10
)
R1 = R2 = R3 = OAc
9
(
R1
) R1 = OAc, R2 = R3 = H; R1 = R3 = OAc, R2 = H; R1 = R2 = R3 = OAc
(11)
(12) R1 = R3 = OAc, R2 = H
13
R
1 = OAc, R2 = R3 = H
11-13
7-10
(
) R
1 = R2 = R3 = OAc
Scheme 1. Synthesis of quasi podands of bile acid derivatives 7–13. Reagents and conditions: (1 or 2 or 3), anhydrous Py, Ac2O, catalytic DMAP, 25 °C, 72 h, yields: 4 (87%), 5
(91%), 6 (89%); (4 or 5 or 6) (1.0 equiv), DBU (1.3 equiv), 1,3,5-tris(bromomethyl)benzene (0.35 equiv), toluene, 90 °C, 24 h, yields: 7 (56%), 8 (46%), 9 (45%); (mixture of 4 and
5 and 6) (1.0 equiv), DBU (1.3 equiv), 1,3,5-tris(bromomethyl)benzene (0.35 equiv), toluene, 90 °C, 24 h, yields: 10 (54%); (4 or 5 or 6) (1.0 equiv), DBU (1.3 equiv), 1,2,4,5-
tetrakis(bromomethyl)benzene (0.25 equiv), toluene, 90 °C, 24 h, yields: 11 (60%), 12 (41%), 13 (32%).
Table 1
PA (probability ‘to be active’) values for predicted biological activities of compounds 7–13
Focal predicted activity (PA >0.85)
Compound
7
8
9
10
11
12
13
Conjunctivitis
0.954
0.917
0.911
0.906
0.886
0.872
0.869
0.867
0.861
0.857
0.853
—
0.946
0.893
—
0.881
0.871
0.876
0.855
—
—
—
—
0.870
0.940
0.914
—
0.890
0.888
0.914
—
—
—
—
—
0.946
0.893
—
0.881
0.871
0.876
0.855
—
—
—
—
0.870
0.948
0.934
0.911
0.906
0.871
0.891
0.858
0.877
0.869
0.866
—
0.940
0.916
—
0.881
0.855
0.894
—
0.862
—
—
0.933
0.932
—
0.890
0.874
0.926
—
—
—
—
—
Antihypercholesterolemic
Respiratory analeptic
Hypercholesterolemic
Ocular toxicity
Hypolipemic
Analeptic
Teratogen
Behavioral disturbance
Embryotoxic
Hepatoprotectant
Cholestasis
—
0.870
—
—
—

4702
T. Pospieszny et al. / Tetrahedron Letters 54 (2013) 4700–4704
Table 2
proaches with the prediction of activity spectra for substances
(PASS) program. It is based on a robust analysis of structure–activ-
ity relationships in a heterogeneous training set, currently includ-
ing about 60,000 biologically active compounds from different
chemical series with about 4500 types of biological activity. Since
only the structural formula of the chemical compound is necessary
to obtain a PASS prediction, this approach can be used at the
earliest stage of an investigation. There are many examples of
Heat of formation (HOF) (kcal/mol) of compounds 7–13
Compound
Heat of formation (kcal/mol)
7
8
9
10
11
12
13
À790.2419
À1056.5849
À1307.3404
À1049.0739
À1060.0673
À1407.2389
À1739.4799
CH2CO
CH2CO
3β-H
CH2CO
3β-H
3β-H
12β-H
7β-H
12β-H
7
8
9
CH2CO
3β-H
3β-H
12β-H
7β-H
10
CH2CO
3β-H
CH2CO
CH2CO
3β-H
3β-H
12β-H
12β-H
7β-H
11
12
13
Figure 1. 1H NMR spectra in the region (5.20–4.30 ppm) of the most characteristic signals of compounds 7–13.

T. Pospieszny et al. / Tetrahedron Letters 54 (2013) 4700–4704
4703
the successful use of the PASS approach leading to new pharmaco-
logical agents.13
studies of chemical compounds. The biological activity spectra
were predicted with PASS for compounds 7–13. We also selected
the types of activity that were predicted for a potential compound
with the highest probability (focal activities) (Table 1). According
to these data the most frequently predicted types of biological
activity are: conjunctivitis, antihypercholesterolemic, hypercholes-
terolemic, ocular toxicity, and hypolipemic.
The structures of all the synthesized compounds were deter-
mined from their 1H and 13C NMR, FT-IR, and ESI-MS spectra.
Moreover, PM5 calculations were performed on all the products.14
Additionally, analyses of the biological prediction activity spectra
for the new esters prepared herein are good examples of in silico
Figure 2. Molecular models of representative compounds 10 and 13 calculated using the PM5 method.

4704
T. Pospieszny et al. / Tetrahedron Letters 54 (2013) 4700–4704
Ragoussis, V. J. Org. Chem. 1973, 38, 4308–4311; (d) Okamura, W. H.; Midland,
The 1H NMR spectra of compounds 7–10 and 11–13 in CDCl3
M. M.; Hammond, M. W.; Rahman, N. A.; Dormanen, M. C.; Nemere, I.; Norman,
A. W. J. Steroid Biochem. Mol. Biol. 1995, 53, 603–613.
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1608; (b) Li, Y.; Dias, R. Chem. Rev. 1997, 97, 283–304; (c) Tamminen, J.;
Kolehmainen, E. Molecules 2001, 6, 21–46.
4. (a) Gao, H.; Dias, J. R. J. Prakt. Chem. 1997, 339, 187–190; (b) Li, Y. X.; Dias, J. R.
Org. Prep. Proced. Int. 1996, 28, 203–209; (c) Hsieh, H. P.; Muller, J. G.; Burrows,
C. J. J. Am. Chem. Soc. 1994, 116, 12077–12078; (d) Guthrie, J. P.; Cullimore, P. A.;
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Joachimiak, R.; Piasecka, M.; Pospieszny, T. Tetrahedron Lett. 2012, 46, 6212–
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Org. Chem. 2001, 2329–2335; (b) Willemen, H. M.; Vermonden, T.; Marcelis, A.
T. M.; Sudhölter, E. J. R. Langmuir 2002, 18, 7102–7106; (c) Valkonen, A.;
Lahtinen, M.; Virtanen, E.; Kaikkonen, S.; Kolehmainen, E. Biosens. Bioelectron.
2004, 20, 1233–1241.
6. Steed, J. W.; Atwood, J. L. Supramolecular Chemistry, 2nd ed.; John Wiley & Sons:
UK, 2009. pp 118–120 and 278–281.
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4151.
show characteristic multiplets in the range of 4.77–4.52 ppm as-
signed to the C3b-H protons of the steroid skeleton, and two
hydrogen singlets ranging from 0.72–0.63 to 0.93–0.91, and char-
acteristic doublets at 0.91–0.81 ppm assigned to CH3-18, CH3-19,
and CH3-21, respectively. In the spectra of compounds 8, 12, 9,
and 13 characteristic broad singlets in the range of 5.10–
5.08 ppm due to the C12b-H protons and doublets at 4.90 ppm
for the C7b-H protons (9 and 13) were observed (Fig. 1). Of partic-
ular interest is compound 10 where two multiplets at 4.76–4.66
and 4.60–4.54 ppm are assigned to the three C3b-H protons, and
three signals due to CH3-18 at 0.72, 0.71, and 0.63 ppm were pres-
ent. Two signals were present at 0.93 and 0.92 ppm due to CH3-19,
and a doublet at 0.91 ppm and a doublet of doublets at 0.81 ppm
were assigned to CH3-21. Moreover, the spectrum of compound
10 showed two broad singlets due to C12b-H at 5.08 and
5.07 ppm, and also two singlets for C7b-H at 4.91 and 4.90 ppm
(Fig. 1). In the 1H NMR spectra of compounds 7–13 the most char-
acteristic signals were observed for the aromatic protons of 1,3,5-
trisubstituted benzene 7–10 and 1,2,4,5-tetrasubstituted benzene
11–13 units. These appeared as singlets at 7.30–7.29 and 7.43–
7.42 ppm for 7–10 and 11–13, respectively. The signals for two
methylene protons of the Ph–CH2–CO group occurred as broad
singlets in the range of 5.18–5.07 ppm.
8. (a) Leska, B.; Pankiewicz, R.; Schroeder, G.; Maia, A. Tetrahedron Lett. 2006, 47,
5673–5676; (b) Maia, A.; Landini, D.; Leska, B.; Schroeder, G. Tetrahedron 2004,
60, 10111–10115; (c) Maia, A.; Landini, D.; Betti, C.; Leska, B.; Schroeder, G.
New J. Chem. 2005, 29, 1195–1198.
9. Huczyn´ ski, A.; Doman´ ska, A.; Paluch, I.; Stefan´ ska, J.; Brzezinski, B.; Bartl, F.
Tetrahedron Lett. 2008, 49, 5572–5575.
10. Kohmoto, S.; Fukui, D.; Nagashima, T.; Kishikawa, K.; Yamamoto, M.; Yamada,
K. Chem. Commun. 1996, 1869–1870.
11. Satyanarayana, T. B. N.; Maitra, U. Chem. Asian J. 2012, 7, 321–329.
12. Example procedure for the synthesis of compound 7: 3a-acetoxy-5b-cholanic
The 13C NMR spectra of compounds 7–13 in CDCl3 showed char-
acteristic signals 12.4–12.0 ppm, 23.4–22.8 ppm, and 18.3–
17.5 ppm, which were assigned to CH3-18, CH3-19, and CH3-21,
respectively. The carbon atoms of the CO2–CH2–Ph unit resonated
in the range of 173.9–173.6 ppm and 65.7–63.1 ppm, assigned to
CO2 and CH2, respectively. The signals due to the acetate C@O
acid (200 mg, 0.48 mmol) was dissolved in anhydrous toluene (5 mL), the
mixture heated for 1 h, and DBU (0.1 mL, 0.62 mmol) was added. The mixture
was heated at reflux for 1 h, followed by the addition of 1,3,5-
tris(bromomethyl)benzene (Aldrich) (60 mg, 0.168 mmol) and heating for an
additional 24 h. The mixture was poured onto ice, extracted with toluene
(10 mL), and washed with H2O (15 mL) and brine (15 mL), and then dried over
anhydrous MgSO4. Evaporation of the solvent and purification of the residue
over silica gel (CHCl3/EtOAc, 50:1) gave 123 mg of product 7 (56%).
group at the 3
the range of 170.6–170.3 ppm.
a or 3a,7a and 3a,7a,12a positions gave signals in
General procedure for the synthesis of compound 10: 3
acid (50 mg, 0.12 mmol), ,12 -diacetoxy-5b-cholanic acid (56.9 mg,
0.12 mmol) and 3 ,7 ,12 -triacetoxy-5b-cholanic acid (63.9 mg, 0.12 mmol)
a-acetoxy-5b-cholanic
3
a
a
The FT-IR spectra of all the compounds (CHCl3) revealed two
strong characteristic bands in the regions 1736–1734 cmÀ1 and
a
a
a
were dissolved in anhydrous toluene (5 mL). The mixture was heated for 1 h,
DBU (3.6 mmol, 0.069 ml) was added and the solution heated under reflux for
1 h. 1,3,5-Tris(bromomethyl)benzene (Aldrich) (42.8 mg, 0.12 mmol) was
added, and the mixture heated for 24 h, then poured onto ice. The mixture
was extracted with toluene (10 mL), and washed with H2O (15 mL) and brine
(15 mL), and then dried over anhydrous MgSO4, then evaporation of the
solvent and purification of the residue over silica gel (CHCl3/EtOAc, 30:1) gave
100 mg of 10 (54%).
1249–1243 cmÀ1, assigned to
m(C@O) and m(C–O), respectively.
PM5 semi–empirical calculations were performed using the
WinMopac 2003 program. The final heats of formation (HOF) for
compounds 7–13 are presented in Table 2. Representative com-
pounds 10 and 13 are shown in Figure 2. The lowest HOF values were
observed for cholic acid derivatives 9 and 13. In general the HOF val-
ues of 1,2,4,5-tetrasubstituted benzene derivatives were lower than
those of 1,3,5-trisubstituted benzene derivatives. This fact can be ex-
plained by an alternating arrangement of the steroid in the structure,
and thus reduction of electrostatic and steric interactions between
the steroid skeletons. This spatial arrangement of bile acids can facil-
itate the formation of stable host–guest complexes.
In conclusion, seven new bile acid esters 7–13 were prepared
from 3
acid, 3
methyl)benzene or 1,2,4,5-tetrakis(bromomethyl)benzene in dry
toluene in the presence of DBU at 95 °C for 24 h. These new com-
pounds were characterized by spectroscopic and molecular struc-
ture methods. These bile acid esters may find applications in
molecular recognition, supramolecular chemistry, and in
pharmacology.
Compound (7): 1H NMR (300 MHz, CDCl3, TMS, ppm): dH 7.30 (s, 3H, ArH), 5.11
(br s, 6H, CH2CO), 4.75–4.69 (m, 3H, 3b-H), 2.03 (s, 9H, 3a-CH3COO), 0.93 (s,
9H, CH3-19), 0.91 (d, J = 6.5 Hz, 9H, CH3-21), 0.63 (s, 9H, CH3-18). 13C NMR
(75 MHz, CDCl3, TMS, ppm): dC 174.31, 173.95, 170.61, 136.92, 127.6, 74.37,
65.72, 65.50, 56.46, 55.97, 42.70, 41.85, 40.37, 40.11, 35.75, 35.33, 35.00, 34.55,
32.22, 31.30, 31.21, 30.97, 30.92, 28.18, 26.99, 26.60, 26.29, 24.16, 23.31, 21.47,
20.80, 18.25, 12.01. FT-IR (CHCl3, film) mmax: 1736, 1448, 1379, 1362, 1243, 756.
ESI-MS (m/z): 1392 [C87H132O12+Na]+, 1408 [C87H132O12+K]+.
Compound (10): 1H NMR (300 MHz, CDCl3, TMS, ppm): dH 7.29 (s, 3H, ArH),
5.11 and 5.10 (br s, 6H, CH2CO), 5.08 and 5.07 (2s, 2H, 12b-H), 4.91 (s, 1H, 7b-
H), 4.76–4.66 (m, 2H, 3b-H), 4.60–4.54 (m, 1H, 3b-H), 2.13 and 2.12 (2s, 6H,
a
a
-acetoxy-5b-cholanic acid, 3
a,12a-diacetoxy-5b-cholanic
,7 ,12 -triacetoxy-5b-cholanic acid, and 1,3,5-tris(bromo-
12a-CH3COO), 2.08 (s, 3H, 7a-CH3COO), 2.05, 2.04 and 2.03 (3s, 9H, 3a-
a
a
CH3COO), 0.93 and 0.92, (2s, 9H, CH3-19), 0.91 (d, J = 6.3 Hz, 3H, CH3-21) and
0.81 (dd, J = 6.3 Hz, 6H, CH3-21), 0.72, 0.71 and 0.63 (s, 9H, CH3-18). 13C NMR
(75 MHz, CDCl3, TMS, ppm): dC 173.90, 173.78, 173.72, 170.63, 170.51, 170,46,
170.42, 170.40, 170.29, 136.92, 136.90, 136.83, 127.69, 75.84, 75.34, 74.35,
74.16, 74.05, 70.66, 65.60, 56.46, 56.00, 49.41, 47.63, 47.42, 45.05, 45.00, 43.37,
42.72, 41.86, 41.80, 40.93, 40.39, 40.13, 37.74, 35.77, 35.66, 35.32, 35.01, 34.69,
34.58, 34.38, 34.32, 34.02, 33.72, 32.24, 31.23, 31.07, 30.94, 30.77, 30.70, 28.87,
28.18, 27.33, 27.17, 27.00, 26.87, 26.62, 26.30, 25.86, 25.63, 25.56, 24.16, 23.42,
23.31, 23.06, 22.80, 22.55, 21.60, 21.45, 21.41, 20.81, 18.26, 17.51, 12.39, 12.22,
12.01. FT-IR (CHCl3, film) mmax: 1734, 1448, 1378, 1363, 1246, 753. ESI-MS (m/
z): 1566 [C93H138O18+Na]+, 1582 [C93H138O18+K]+.
Supplementary data
13. (a) www.pharmaexpert.ru/PASSOnline/.; (a) Poroikov, V. V.; Filimonov, D. A.;
Borodina, Y. V.; Lagunin, A. A.; Kos, A. J. Chem. Inf. Comput. Sci. 2000, 40,
1349–1355; (b) Poroikov, V. V.; Filimonov, D. A. J. Comput. Aided Mol. Des.
2003, 16, 819–824; (c) Poroikov, V. V.; Filimonov, D. A. In Predictive
Toxicology; Helma, C., Ed.; Taylor and Francis, 2005; pp 459–478; (d)
Stepanchikova, A. V.; Lagunin, A. A.; Filimonov, D. A.; Poroikov, V. V. Curr.
Med. Chem. 2003, 10, 225–233.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.06.m
096.
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